Quinoxalinyl amide derivatives

ABSTRACT

A compound of the formula                    
     or the pharmaceutically acceptable salt thereof; wherein R 1 , R 2 , R 3  and R 4  are as defined above useful to treat inflammation and other immune disorders.

The present application claims the benefit of U.S. ProvisionalApplication No. 60/180,159, filed Feb. 4, 2000.

BACKGROUND OF THE INVENTION

The present invention relates to novel hexanoic acid derivatives,methods of use and pharmaceutical compositions containing them.

The compounds of the invention are potent and selective inhibitors ofMIP-1α binding to its receptor CCR1 found on inflammatory andimmunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1receptor is also sometimes referred to as the CC-CKR1 receptor. Thesecompounds also inhibit MIP-1α (and the related chemokines shown tointeract with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1cells and human leukocytes and are potentially useful for the treatmentor prevention of autoimmune diseases (such as rheumatoid arthritis, typeI diabetes (recent onset), inflammatory bowel disease, optic neuritis,psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, andvasculitis), acute and chronic inflammatory conditions (such asosteoarthritis, adult Respiratory Distress Syndrome, RespiratoryDistress Syndrome of infancy, ischemia reperfusion injury, andglomerulonephritis), allergic conditions (such as asthma and atopicdermatitis), infection associated with inflammation (such as viralinflammation (including influenza and hepatitis) and Guillian-Barre),chronic bronchitis, xeno-transplantation, transplantation tissuerejection (chronic and acute), organ rejection (chronic and acute),atherosclerosis, restenosis, HIV infectivity (co-receptor usage), andgranulomatous diseases (including sarcoidosis, leprosy andtuberculosis).

MIP-1α and RANTES are soluble chemotactic peptides (chemokines) whichare produced by inflammatory cells, in particular CD8+ lymphocytes,polymorphonuclear leukocytes (PMNS) and macrophages, J. Biol. Chem., 270(30) 29671-29675 (1995). These chemokines act by inducing the migrationand activation of key inflammatory and immunomodulatory cells. Elevatedlevels of chemokines have been found in the synovial fluid of rheumatoidarthritis patients, chronic and rejecting tissue transplant patients andin the nasal secretions of allergic rhinitis patients following allergenexposure (Teran, et al., J. Immunol., 1806-1812 (1996), and Kuna et al.,J. Allergy Clin. Immunol. 321 (1994)). Antibodies which interfere withthe chemokine/receptor interaction by neutralizing MIP1α or genedisruption have provided direct evidence for the role of MIP-1α andRANTES in disease by limiting the recruitment of monocytes and CD8+lymphocytes (Smith et al., J. Immunol, 153, 4704 (1994) and Cook et al.,Science, 269, 1583 (1995)). Together this data demonstrates that CCR1antagonists would be an effective at treatment of several immune baseddiseases. The compounds described within are potent and selectiveantagonists of CCR1.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula

or the pharmaceutically acceptable salt thereof; wherein

R¹ is (C₂-C₉)heteroaryl optionally substituted with one or moresubstituents independently selected from the group consisting ofhydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionally substituted withone or more fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alky]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

R² is phenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—,(C₃-C₁₀)cycloalkyl-(CH₂)_(m)—, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl-(CH₂)_(m)—, wherein m is an interger from zero tofour; wherein each of said phenyl, naphthyl, (C₃-C₁₀)cycloalkyl or(C₂-C₉)heteroaryl moieties of said phenyl-(CH₂)_(m)—,naphthyl-(CH₂)_(m)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(m)— or(C₂-C₉)heteroaryl-(CH₂)_(m)— groups may optionally be substituted withone or more substituents independently selected from hydrogen,deuterium, halo, CN, (C₁-C₆)alkyl optionally substituted with one ormore fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,phenoxy, benzyloxy, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and(C₂-C₉)heteroaryl;

R³ is hydrogen, deuterium, (C₁-C₁₀)alkyl, (C₃-C₁₀)cycloalkyl-(CH₂)_(n)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(n)—, (C₂-C₉)heteroaryl-(CH₂)_(n)— oraryl-(CH₂)_(n)—; wherein n is an interger from zero to six;

wherein said R³ (C₁-C₁₀)alkyl group may optionally be substituted withone or more substituents, independently selected from hydrogen,deuterium, halo, CN, (C₁-C₆)alkyl optionally substituted with one ormore fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C∇O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂-(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; andwherein any of the carbon-carbon single bonds of said (C₁-C₁₀)alkyl mayoptionally be replaced by a carbon-carbon double bond;

wherein the (C₃-C₁₀)cycloalkyl moiety of said R³(C₃-C₁₀)cycloalkyl-(CH₂)_(n)— group may optionally be substituted by oneto three substitutents independently selected from the group consistingof hydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionally substitutedwith one or more fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy optionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl—(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein the (C₂-C₉)heterocycloalkyl moiety of said R³(C₂-C₉)heterocycloalkyl-(CH₂)_(n)—group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur,oxygen, >S(═O), >SO₂ or >NR⁶, wherein said (C₂-C₉)heterocycloalkylmoiety of said (C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may optionallybe substituted on any of the ring carbon atoms capable of forming anadditional bond with a substituent independently selected from the groupconsisting of hydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionallysubstituted with one or more fluorine atoms, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one ormore fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein the (C₂-C₉)heteroaryl moiety of said R³(C₂-C₉)heteroaryl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur or oxygenwherein said (C₂-C₉)heteroaryl moiety of said(C₂-C₉)heteroaryl-(CH₂)_(n)— group may optionally be substituted on anyof the ring carbon atoms capable of forming an additional bond with asubstituent selected from the group consisting of hydrogen, deuterium,halo, CN, (C₁-C₆)alkyl optionally substituted with one or more fluorineatoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionallysubstituted with one or more fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; and

wherein said aryl moiety of said R³ aryl-(CH₂)_(n)— group is optionallysubstituted phenyl or naphthyl, wherein said phenyl and naphthyl mayoptionally be substituted with from one to three substituentsindependently selected from the group consisting of hydrogen, deuterium,halo, CN, (C₁-C₆)alkyl optionally substituted with one or more fluorineatoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionallysubstituted with one or more fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

or R³ and the carbon to which it is attached form a five to sevenmembered carbocyclic ring, wherein any of the carbon atoms of said fivemembered carbocyclic ring may optionally be substituted with asubstituent selected from the group consisting of hydrogen, deuterium,halo, CN, (C₁-C₆)alkyl optionally substituted with one or more fluorineatoms (preferably one to three fluorine atoms), hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one ormore fluorine atoms (preferably one to three fluorine atoms),(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl(O═C)—O—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₉)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;wherein one of the carbon-carbon bonds of said five to seven memberedcarbocyclic ring may optionally be fused to an optionally substitutedphenyl ring, wherein said substitutents may be independently selectedfrom hydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionally substitutedwith one or more fluorine atoms (preferably one to three fluorineatoms), hydroxy, hydroxy-(C₁-C₈)alkyl, (C₁-C₆)alkoxy optionallysubstituted with one or more fluorine atoms (preferably one to threefluorine atoms), (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; and

R⁴ is (C₂-C₉)heteroaryl , (C₂-C₉)heterocycloalkyl, R⁵R⁶N-sulfonyl or agroup of the formula

wherein R⁵ is hydrogen, deuterium, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C═O)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(p)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(p)—, (C₂-C₉)heteroaryl-(CH₂)_(p)—,phenyl-(CH₂)_(p)—, or naphthyl-(CH₂)_(p)—, wherein p is an integer fromzero to four; wherein said (C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl,phenyl and naphthyl groups of said (C₂-C₉)heterocycloalkyl-(CH₂)_(p)—,(C₂-C₉)heteroaryl-(CH₂)_(p)—, phenyl-(CH₂)_(p)—, or naphthyl-(CH₂)_(p)—may be optionally substituted on any of the ring atoms capable ofsupporting an additional bond with a substituent selected from the groupconsisting of hydrogen, halo, CN, (C₁-C₆)alkyl optionally substitutedwith one or more fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy optionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₈)alkyl, (C₁-C₆) alkyl(O═C)—,(C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂ amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₈)alkyl]₂N—(C═O)—, H₂N(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl,H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH, (C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl (C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₈)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a (C₂-C₉)heterocycloalkyl group wherein any of the ring atoms ofsaid (C₂-C₉)heterocycloalkyl group may optionally be substituted with asubstituent selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl optionally substituted with one or more fluorine atoms,hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted withone or more fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂ amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino (C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

R⁶ is hydrogen, deuterium, (C₁-C₆)alkyl or amino;

X is NR⁷ or S wherein R⁷ is defined as R⁴ above; and

with the proviso that when R⁴ is a five-membered heterocyclic group,either R² or R³ must be substituted by a functional group other than(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl, benzofuryl, indolyl,azacycloalkyl, azabicycloalkyl or benzopiperidinyl.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3- naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

Unless otherwise indicated, the alkyl and alkenyl groups referred toherein, as well as the alkyl moieties of other groups referred to herein(e.g., alkoxy), may be linear or branched, and they may also be cyclic(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl)or be linear or branched and contain cyclic moieties. Unless otherwiseindicated, halogen includes fluorine, chlorine, bromine, and iodine.

(C₃-C₁₀)Cycloalkyl when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl etc.

(C₂-C₉)Heterocycloalkyl when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skillin the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a sp³ hybridizednitrogen heteroatom.

(C₂-C₉)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl,pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl,tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill inthe art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

Aryl when used herein refers to phenyl or naphthyl.

The compounds of this invention include all conformational isomers(e.g., cis and trans isomers) and all optical isomers of compounds ofthe formula I (e.g., enantiomers and diastereomers), as well as racemic,diastereomeric and other mixtures of such isomers.

Preferred compounds of the of formula I include those with thestereochemistry depicted in formula

Preferred compounds of the formula I include those wherein R¹ isoptionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl,6,7-dihydro-5H-[1]pyrindinyl, benzothiazolyl, indolyl, pyrazinyl,benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalenyl,quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl orquinolinyl, more preferably pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl,pyridin-2-yl, 6,7-dihydro-5H-[1]pyrindin-3-yl, benzothiazol-2-yl,indol-2-yl, pyrazin-2-yl, benzoimidazol-2-yl, benzofuran-2-yl,benzo[b]thiophen-2-yl, naphthalen-2-yl, quinoxalin-2-yl,quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl,5,6,7,8-tetrahydro-quinolin-3-yl, quinolin-2-yl, quinolin-3-yl,quinolin-4-yl or quinolin-6-yl, most preferably quinoxalin-6-yl,quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, quinolin-4-yl orquinolin-6-yl.

Other preferred compounds of formula I include those wherein R² isoptionally substituted phenyl, benzyl, naphthyl, cyclohexyl, thienyl,thiazolyl, pyridyl, oxazolyl, furanyl, or thiophenyl; wherein saidsubstituents are independently selected from hydrogen, halo,(C₁-C₆)alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, —C(═O)—OH,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C═O)—, NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂N—(C═O)—, H₂N(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl,H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH, (C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, phenoxy, and benzyloxy.

Other preferred compounds of formula I include those wherein R³ isoptionally substituted (C₁-C₁₀)alkyl, benzyl, pyranyl or(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—, wherein any of the carbon—carbon singlebonds of said (C₁-C₁₀)alkyl may be optionally replaced by acarbon—carbon double bond; more preferably optionally substitutedn-butyl, isobutyl, n-pentyl, 3-methyl-butyl, 2-methyl-pentyl, allyl,cyclopentyl, cyclohexyl or cycloheptyl, more preferably wherein thesubstituent is fluoro, (C₁-C₆)alkyl or hydroxy.

Examples of specific preferred compounds of the formula I are thefollowing:

Quinoxaline-2-carboxylic acid[1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[1(S)-benzyl-2(S),7-dihydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-4(R)-sulfamoyl-octyl]-amide;

Quinoxaline-2-carboxylic acid(1(S)-benzyl-2(S),7-dihydroxy-7-methyl-4(R)-sulfamoyl-octyl)-amide;

Quinoxaline-2-carboxylic acid[7-fluoro-1(S)-(3-fluoro-benzyl)-2(S),-hydroxy-7-methyl-4(R)-sulfamoyl-octyl]-amide;

Quinoxaline-2-carboxylic acid(1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-sulfamoyl-octyl)-amide;

Quinoxaline-2-carboxylic acid[1(S)-(3-fluoro-benzyl)-(2(S),7-dihydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;

Quinoxaline-2-carboxylic acid(1(S)-benzyl-2(S)-7-dihydroxy-7-methyl-4(R)-methylsulfamoyl-octyl)-amide;

Quinoxaline-2-carboxylic acid[(S)-(3-fluoro-benzyl)-2(S),7-hydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[I(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;

Quinoxaline-2-carboxylic acid [4(R)-(4-chloro-1 H-imidazol-2-yl )-1(S)-(3-fluoro-benzyl)-2(S),-7-fluoro-benzyl)-2(S)-hydroxy-dihydroxy-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[1(S)-benzyl-4(R)(4-chloro-1H-imidazol-2-yl)-2(S),-7-hydroxy-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[4(R)-(4-chloro-1H-imidazol-2-yl)-7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[1(S)-benzyl-4(R)(4-chloro-1H-imidazol-2-yl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[1(S)-(3-fluoro-benzyl)-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

Quinoxaline-2-carboxylic acid[1(S)-benzyl-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-7-dihydroxy-7-methyl-octyl]amide;

Quinoxaline-2-carboxylic acid[7-fluoro-1(S)-(3-fluoro-benzyl)-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-hydroxy-7-methyl-octyl]-amide;and

Quinoxaline-2-carboxylic acid[1(S)-benzyl-7-fluoro-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-hydroxy-7-methyl-octyl]amide.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected from autoimmunediseases (such as rheumatoid arthritis, type I diabetes (recent onset),inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute andchronic inflammatory conditions (such as osteoarthritis, adultrespiratory distress syndrome, Respiratory Distress Syndrome of infancy,ischemia reperfusion injury, and glomerulonephritis), allergicconditions (such as asthma and atopic dermatitis), infection associatedwith inflammation (such as viral inflammation (including influenza andhepatitis) and Guillian-Barre), chronic bronchitis,xeno-transplantation, transplantation tissue rejection, atherosclerosis,restenosis, HIV infectivity (co-receptor usage), and granulomatousdiseases (including sarcoidosis, leprosy and tuberculosis). in a mammal,preferably a human, comprising an amount of a compound of the formula Ior a pharmaceutically acceptable salt thereof effective in treating orpreventing such disorder or condition and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by inhibiting MIP-1α binding to the receptor CCR1 in a mammal,preferably a human, comprising an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and a pharmaceutically acceptablecarrier. Examples of such disorders and conditions are those enumeratedin the preceding paragraph.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from autoimmune diseases(such as rheumatoid arthritis, type I diabetes (recent onset),inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute andchronic inflammatory conditions (such as osteoarthritis, adultrespiratory distress syndrome, Respiratory Distress Syndrome of infancy,ischemia reperfusion injury, and glomerulonephritis), allergicconditions (such as asthma and atopic dermatitis), infection associatedwith inflammation (such as viral inflammation (including influenza andhepatitis) and Guillian-Barre), chronic bronchitis,xeno-transplantation, transplantation tissue rejection, atherosclerosis,restenosis, HIV infectivity (co-receptor usage), and granulomatousdiseases (including sarcoidosis, leprosy and tuberculosis) in a mammal,preferably a human, comprising administering to a mammal in need of suchtreatment or prevention an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingor preventing such disorder or condition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byantagonizing the CCR1 receptor in a mammal, preferably a human,comprising administering to a mammal in need of such treatment orprevention an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingor preventing such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected from autoimmunediseases (such as rheumatoid arthritis, type I diabetes (recent onset),inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute andchronic inflammatory conditions (such as osteoarthritis, adultrespiratory distress syndrome, Respiratory Distress Syndrome of infancy,ischemia reperfusion injury, and glomerulonephritis), allergicconditions (such as asthma and atopic dermatitis), infection associatedwith inflammation (such as viral inflammation (including influenza andhepatitis) and Guillian-Barre), chronic bronchitis,xeno-transplantation, transplantation tissue rejection, atherosclerosis,restenosis, HIV infectivity (co-receptor usage), and granulomatousdiseases (including sarcoidosis, leprosy and tuberculosis) in a mammal,preferably a human, comprising a CCR1 receptor antagonizing effectiveamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by antagonizing the CCR1 receptor in a mammal, preferably ahuman, comprising a CCR1 receptor antagonizing effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from autoimmune diseases(such as rheumatoid arthritis, type I diabetes (recent onset),inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute andchronic inflammatory conditions (such as osteoarthritis, adultrespiratory distress syndrome, Respiratory Distress Syndrome of infancy,ischemia reperfusion injury, and glomerulonephritis), allergicconditions (such as asthma and atopic dermatitis), infection associatedwith inflammation (such as viral inflammation (including influenza andhepatitis) and Guillian-Barre), chronic bronchitis,xeno-transplantation, transplantation tissue rejection, atherosclerosis,restenosis, HIV infectivity (co-receptor usage), and granulomatousdiseases (including sarcoidosis, leprosy and tuberculosis) in a mammal,preferably a human, comprising administering to a mammal in need of suchtreatment or prevention a CCR1 receptor antagonizing effective amount ofa compound of formula I, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R¹, R²,R³ and R⁴ in the reaction Schemes and the discussion that follow aredefined as above.

Compounds of formula I may be prepared by methods described in WO98/38167, which is incorporated by reference in its entirety.

In reaction 1 of Scheme 1, the alcohol compound of formula XII isconverted to the corresponding acetate compound of formula XI byreacting XII with acetic anhydride in the presence of4-dimethylaminopyridine (DMAP) and pyridine. The reaction 1 stirred at atemperature between about 0° C. to about room temperature, preferablyabout 0° C., for a time period between about 1 hour to about 3 hours,preferably about 2 hours.

In reaction 2 of Scheme 1, the compound of formula XI is converted tothe corresponding compound of formula X by reacting XI withN,N-dimethylformamide dimethyl acetal in the presence of a polar proticsolvent, such as methanol. The reaction is stirred at a temperaturebetween about 40° C. to about 60° C., preferably about 50° C., for atime period between about 30 minutes to about 2 hours, preferably about1 hour.

In reaction 3 of Scheme 1, the compound of formula X is converted to thecorresponding triazole compound of formula IX by reacting X withhydrazine in the presence of acetic acid. The reaction is stirred at atemperature between about 40° C. to about 60° C., preferably about 50°C., for a time period between about 30 minutes to about 2 hours,preferably about 1 hour.

In reaction 4 of Scheme 1, the compound of formula IX is converted tothe corresponding compound of formula II by deprotecting IX withpotassium carbonate in the presence of methanol at room temperatureovernight.

In reaction 1 of Scheme 2, the lactone compound of formula XIV isconverted to the corresponding hydrazide compound of formula XII byreacting XIV with hydrazine in a polar protic solvent, such as methanol.The reaction is stirred at room temperature overnight.

In reaction 2 of Scheme 2, the hydrazine compound of formula XIII isconverted to the corresponding 1,2,4-oxadiazole compound of formula IIIby reacting XIII with cyanogen bromide in the presence of dioxane andwater. The reaction is heated to reflux for a time period between about30 minutes to about 2 hours, preferably about 1 hour.

In reaction 3 of Scheme 2, the hydrazide compound of formula XIII isconverted to the corresponding compound of formula IV by reacting XIIIwith CDI in the presence of a base, such as triethylamine, and a polaraprotic solvent, such as tetrahydrofuran. The reaction is stirred atroom temperature for a time period between about 10 hours to about 20hours, preferably overnight.

In reaction 1 of Scheme 3, the lactone compound of formula XVIII isconverted to the corresponding compound of formula XVII by reactingXVIII with aminoacetaldehyde dimethyl acetal in the presence of dioxane.The reaction is stirred overnight at a temperature between about 30° C.to about 70° C., preferably about 50° C.

In reaction 2 of Scheme 3, the alcohol compound of formula XVII isconverted to the corresponding acetate compound of formula XVI accordingto the procedure described above in reaction 1 of Scheme 1.

In reaction 3 of Scheme 3, the compound of formula XVI is converted tothe corresponding imidazole compound of formula XV by reacting XVI withammonium acetate in the presence of acetic acid. The reaction is stirredat a temperature between about 105° C. to about 125° C., preferablyabout 115° C., for a time period between about 3 hours to about 5 hours,preferably about 4 hours.

In reaction 4 of Scheme 3, the compound of formula XV is converted tothe corresponding compound of formula V according to the proceduredescribed above in reaction 4 of Scheme 1.

In reaction 1 of Scheme 4, the epoxide compound of formula XXI isconverted to the corresponding compound of formula XX by reacting XXIwith a compound of the formula, CHR³R⁴, in the presence of a base, suchas n-butyllithium, and a polar aprotic solvent, such as tetrahydrofuran.The reaction is carried out at a temperature between about −78° C. toabout 0° C., preferably about −78° C., for a time period between about 1hours to about 4 hours, preferably about 2 hours.

In reaction 2 of Scheme 4, the compound of formula XX is converted tothe corresponding compound of formula XIX by removal of thecarbobenzyloxy protecting group through hydrogenation of XX in thepresence of palladium on carbon and a polar protic solvent, such asethanol. The reaction is carried out at a temperature between about 0°C. to room temperature, preferably room temperature, for a time periodbetween about 1 hour to about 24 hours, preferably about 15 hours.

In reaction 3 of Scheme 4, the compound of formula XIX is converted tothe corresponding compound of formula I by reacting XIX with a compoundof the formula, R¹—CO—Cl, in the presence of a base, such astriethylamine, and a polar aprotic solvent, such as methylene chloride.The reaction is carried out at a temperature between about −20° C. toabout 40° C., preferably about 0° C., for a time period between about 1hour to about 24 hours, preferably about 2 hours.

In reaction 1 of Scheme 5, the compound of formula XXVI is converted tothe corresponding compound of formula XXV according to the proceduredescribed above in reaction 1 of Scheme 1.

In reaction 2 of Scheme 5, the amide compound of formula XXV isconverted to the thioacetamide compound of formula XXIV by reacting XXVwith Lawesson's Reagent,[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide],in the presence of a polar aprotic solvent, such as tetrahydrofuran. Thereaction is carried out at a temperature between about 0° C. to about60° C., preferably about 25 ° C, for a time period between about 1 hourto about 24 hours, preferably about 5 hours.

In reaction 3 of Scheme 5, the thioacetamide compound of formula XXIV isconverted to the corresponding compound of formula XXIII by firsttreating XXIV with methyl iodide, followed by reacting the compound soformed with ammonia in methyl alcohol. The reaction is carried out at atemperature between about 0° C. to about 60° C., preferably about 25°C., for a time period between about 1 hour to about 24 hours, preferablyabout 15 hours.

In reaction 4 of Scheme 5, the compound of formula XXIII is converted tothe corresponding compound of formula XXII by reacting XXII with (a) R⁸sulfonyl chloride when R⁷ is R⁸S(O)₂; (b) cyanogen bromide when R⁷ iscyano; (c) L—N═C═O when R⁷ is an amide and L is a leaving group; or (d)an acyl chloride compound of the formula, R⁸—CO—Cl, when R⁷ is R⁸C(O).

In reaction 5 of Scheme 5, the compound of formula XXII is converted tothe corresponding compound of formula VI according to the proceduredescribed above in reaction 1 of Scheme 1.

In reaction 1 of Scheme 6, the lactone of formula XXXII is converted tothe corresponding compound of formula XXXI by reacting XXXII with abase, such as lithium hydroxide, in the presence of a mixture of waterand a polar aprotic solvent, such as tetrahydrofuran. The reaction iscarried out at a temperature between about 0° C. to about 60° C.,preferably about 25° C., for a time period between about 1 hour to about24 hours, preferably about 2 hours.

In reaction 2 of Scheme 6, the compound of formula XXXI is converted tothe corresponding compound of formula XXX by reacting XXXI withtert-butyldimethylsilyl chloride in the presence of imidazole and polarprotic solvent, such as dimethylformamide. The reaction is carried outat a temperature between about 0° C. to about 60° C., preferably about25° C., for a time period between about 1 day to 7 days, preferably 1day.

In reaction 3 of Scheme 6, the compound of formula XXX is converted tothe corresponding compound of formula XXIX by reacting XXX with acompound of the formula

in the presence of 1-hydroxybenzotriazole hydrate,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and a polar aproticsolvent, such as methylene chloride. The reaction is carried out at atemperature between about 0° C. to about 30° C., preferably about 25°C., for a time period between about 1 hour to about 24 hours, preferablyabout 25 hours.

In reaction 4 of Scheme 6, the compound of formula XXIX is converted tothe corresponding oxazole compound of the formula XXVII by firstoxidizing XXIX with the Dess-Martin periodinane oxidation reagent of theformula

followed by treating the compound so formed with triphenylphosphine,triethylamine, hexachloroethane and a polar aprotic solvent, such asmethylene chloride. The reaction is carried out at a temperature betweenabout 0° C. to about 40° C., preferably about 25° C., for a time periodbetween about 5 hours to about 24 hours, preferably about 15 hours.

In reaction 5 of Scheme 6, the compound of formula XXIX is converted tothe corresponding oxazoline compound of formula XXVIII by treating XXIXwith triphenylphosphine, hexachloroethane, triethylamine and a polaraprotic solvent, such as methylene chloride. The reaction is carried outat a temperature between about 0° C. to about 40° C., preferably about25° C., for a time period between about 5 hours to about 24 hours,preferably about 15 hours.

In reaction 6 of Scheme 6, the compound of formula XXVII is converted tothe corresponding compound of formula VII by treating XXVII withtert-butyl ammonium fluoride. The reaction is carried out at atemperature between about 0° C. to about 40° C., preferably about 25°C., for a time period between about 1 hour to about 24 hours, preferablyabout 2 hours.

In reaction 7 of Scheme 6, the compound of formula XXVIII is convertedto the corresponding compound of formula VIII according to the proceduredescribed above in reaction 6 of Scheme 6.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula I. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

Compounds of the formula I and their pharmaceutically acceptable salts(hereinafter also referred to, collectively, as “the active compounds”)are potent antagonists of the CCR1 receptors. The active compounds areuseful in the treatment or prevention of autoimmune diseases (such asrheumatoid arthritis, type I diabetes (recent onset), inflammatory boweldisease, optic neuritis, psoriasis, multiple sclerosis, polymyalgiarheumatica, uveitis, and vasculitis), acute and chronic inflammatoryconditions (such as osteoarthritis, adult respiratory distress syndrome,Respiratory Distress Syndrome of infancy, ischemia reperfusion injury,and glomerulonephritis), allergic conditions (such as asthma and atopicdermatitis), infection associated with inflammation (such as viralinflammation (including influenza and hepatitis) and Guillian-Barre),chronic bronchitis, xeno-transplantation, transplantation tissuerejection, atherosclerosis, restenosis, HIV infectivity (co-receptorusage), and granulomatous diseases (including sarcoidosis, leprosy andtuberculosis).

The activity of the compounds of the invention can be assessed accordingto procedures know to those of ordinary skill in the art. Examples ofrecognized methods for determining CCR1 induced migration can be foundin Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M.,Strober, W. editors: Current Protocols In Immunology, 6.12.1-6.12.3.(John Wiley and Sons, New York, 1991). One specific example of how todetermine the activity of a compound for inhibiting migration isdescribed in detail below.

Chemotaxis Assay

The ability of compounds to inhibit the chemotaxis to various chemokinescan be evaluated using standard 48 or 96 well Boyden Chambers with a 5micron polycarbonate filter. All reagents and cells can be prepared instandard RPMI (BioWhitikker Inc.) tissue culture medium supplementedwith 1 mg/ml of bovine serum albumin. Briefly, MIP-1α (Peprotech, Inc.,P.O. Box 275, Rocky Hill N.J.) or other test agonists, were placed intothe lower chambers of the Boyden chamber. A polycarbonate filter wasthen applied and the upper chamber fastened. The amount of agonistchosen is that determined to give the maximal amount of chemotaxis inthis system (e.g., 1 nM for MIP-1α should be adequate).

THP-1 cells (ATCC TIB-202), primary human monocytes, or primarylymphocytes, isolated by standard techniques can then be added to theupper chambers in triplicate together with various concentrations of thetest compound. Compound dilutions can be prepared using standardserological techniques and are mixed with cells prior to adding to thechamber.

After a suitable incubation period at 37 degrees centigrade (e.g. 3.5hours for THP-1 cells, 90 minutes for primary monocytes), the chamber isremoved, the cells in the upper chamber aspirated, the upper part of thefilter wiped and the number of cells migrating can be determinedaccording to the following method.

For THP-1 cells, the chamber (a 96 well variety manufactured byNeuroprobe) can be centrifuged to push cells off the lower chamber andthe number of cells can be quantitated against a standard curve by acolor change of the dye fluorocein diacetate.

For primary human monocytes, or lymphocytes, the filter can be stainedwith Dif Quik® dye (American Scientific Products) and the number ofcells migrating can be determined microscopically.

The number of cells migrating in the presence of the compound aredivided by the number of cells migrating in control wells (without thecompound). The quotant is the % inhibition for the compound which canthen be plotted using standard graphics techniques against theconcentration of compound used. The 50% inhibition point is thendetermined using a line fit analysis for all concentrations tested. Theline fit for all data points must have an coefficient of correlation (Rsquared) of >90% to be considered a valid assay.

All of the compounds of the invention that were tested had IC₅₀ of lessthan 25 μM, in the Chemotaxis assay.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., rheumatoid arthritis) in the average adult human are preferablyarranged so that each metered dose or “puff” of aerosol contains 20 μgto 1000 μg of the compound of the invention. The overall daily dose withan aerosol will be within the range 0.1 mg to 1000 mg. Administrationmay be several times daily, for example 2, 3, 4 or 8 times, giving forexample, 1, 2 or 3 doses each time.

The active agents can be formulated for sustained delivery according tomethods well known to those of ordinary skill in the art. Examples ofsuch formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598,4,173,626, 3,119,742, and 3,492,397.

The compounds of the invention can also be utilized in combinationtherapy with other therapeutic agents such as with T-cellimmunosuppressant agents such as cyclosporin A and FK-506, with steroidsparing agents such as Cellcept®, or with classical anti-inflammatoryagents (e.g. cyclooxygenase/lipoxegenase inhibitors) such as tenidap,aspirin, acetaminophen, naproxen and piroxicam.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (δ) and are referenced to the deuteriumlock signal from the sample solvent (deuteriochloroform unless otherwisespecified). Commercial reagents were utilized without furtherpurification. THF refers to tetrahydrofuran. DMF refers toN,N-dimethylformamide. Chromatography refers to column chromatographyperformed using 32-63 mm silica gel and executed under nitrogen pressure(flash chromatography) conditions. Low Resolution Mass Spectra (LRMS)were recorded on either a Hewlett Packard 5989®, utilizing chemicalionization (ammonium), or a Fisons (or Micro Mass) Atmospheric PressureChemical Ionization (APCI) platform which uses a 50/50 mixture ofacetonitrile/water with 0.1% formic acid as the ionizing agent. Room orambient temperature refers to 20-25° C. All non-aqueous reactions wererun under a nitrogen atmosphere for convenience and to maximize yields.Concentration at reduced pressure means that a rotary evaporator wasused. The names for the compounds of the invention were created by theAutonom 2.0 PC-batch version from Beilstein Informationssysteme GmbH(ISBN 3-89536-976-4).

EXAMPLE 1

Quinoxaline-2-carboxylic acid[1-(3-fluoro-benzyl)-2,7-dihydroxy-4-(1H-imidazol-2-yl)-7-methyl-octyl]-amide

To a solution of trifluoro-acetic acid3-(5-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-2-oxo-tetrahydro-furan-3-yl)-1,1-dimethyl-propylester (212 mg, 0.378 mmol) in methanol (4 mL) was addedaminoacetalaldehyde dimethyl acetal (0.375 mL, 3.44 mM) and stirred for14 days. The reaction was concentrated to provide the crude productwhich was purified by silica get chromatography to yield the titlecompound (197 mg, 91%).

Acetic acid3-(2,2-dimethoxy-ethylcarbamoyl)-1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino}-ethyl]-6-hydroxy-6-methyl-heptylester

To a solution of quinoxaline-2-carboxylic acid[4-(2,2-dimethoxy-ethylcarbamoyl)-1-(3-fluoro-benzyl)-2,7-dihydroxy-7-methyl-octyl]-amide(192 mg, 0.336 mmol) in pyridine (0.6 mL) was addeddimethylaminopyridine (DMAP) (10 mg, 0.082 mmol) and acetic anhydride(0.093 mL, 0.984 mmol). The resulting solution was stirred for 3 hoursthen diluted with methylene chloride and washed with 1 M hydrochloricacid. The organic layer was dried over sodium sulfate, filtered andconcentrated to give the title compound as a white foam (198 mg, 96%).

Acetic acid1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-6-hvdroxy-3-(1H-imidazol-2-yl)-6-methyl-heptylester

To a solution of acetic acid3-(2,2-dimethoxy-ethylcarbamoyl)-1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-6-hydroxy-6-methyl-heptylester (150 mg, 0.245 mmol) in acetic acid (2 mL) was added ammoniumacetate (1.5 g 19.5 mmol). The resulting mixture was heated to 115° C.for 3 hours, cooled to ambient temperature and diluted with ethylacetate. The solution was then neutralized with saturated aqueous sodiumbicarbonate. The organic layer was dried over sodium sulfate, filteredand concentrated. Chromatography on silica gel gave the title compound(22.5 mg, 17%).

Quinoxaline-2-carboxylic acid[1-(3-fluoro-benzyl)-2,7-dihydroxy-4-(1H-imidazol-2-yl)-7-methyl-octyl]-amide

To a solution of acetic acid1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-6-hydroxy-3-(1H-imidazol-2-yl)-6-methyl-heptylester (32 mg, 0.058 mmol) in methanol (1 mL) was added potassiumcarbonate (100 mg, 0.724 mmol). The resulting solution was stirred for 2hours then concentrated. The crude product was dissolved in a mixture ofmethylene chloride and water. The organic layer was dried over sodiumsulfate, filtered and concentrated. Chromatography on silica gel gavethe title compound (32 mg, >100%).

The title compounds for examples 2-15 were prepared by a methodanalogous to that described in Example 1.

EXAMPLE R¹ R² R³ R⁴ 2

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EXAMPLE 16

Quinoxaline-2-carboxylic acid[1-benzyl-7-fluoro-2-hydroxy-7-methyl-4-(4H-[1,2,4]triazol-3-yl)-octyl]-amide

Acetic acid3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptylester

To a solution of quinoxaline-2-carboxylic acid(1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide (1.01 g,2.14 mmol) in pyridine (4 mL) was added dimethylaminopyridine (DMAP) (65mg, 0.533 mmol) and acetic anhydride (0.400 mL, 4.23 mmol). Theresulting solution was stirred for 2 hours, then diluted with methylenechloride and washed with 1 M hydrochloric acid. The organic layer wasdried over sodium sulfate, filtered and concentrated to give the titlecompound as a white foam (1.16 g, >100%).

Acetic acid3-(dimethylaminomethylene-carbamoyl)-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptylester

A solution of acetic acid3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptylester (522 mg, 1.03 mmol) in N,N-dimethylformamide dimethyl acetal (2mL) was heated to 50° C. for two hours, cooled to ambient temperatureand diluted with methylene chloride and water. The organic layer waswashed with saturated aqueous sodium chloride, dried over sodiumsulfate, filtered and concentrated to give the title compound as a whitefoam (580 mg, 100%).

Acetic acid6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-3-(4H-[1,2,4]triazol-3-yl)-heptylester

To a solution of acetic acid3-(dimethylaminomethylene-carbamoyl)-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptylester (580 mg, 1.03 mmol) in acetic acid (2.5 mL) was added hydrazine(35 wt. % in water, 0.040 mL). The resulting solution was heated to 50°C. for 4 hours, cooled to ambient temperature, diluted with ethylacetate, and neutralized with saturated aqueous sodium bicarbonate. Theorganic later was dried over sodium sulfate, filtered, and concentratedto give the title compound as a white foam (580 mg, >100%).

Quinoxaline-2-carboxylic acid[1-benzyl-7-fluoro-2-hydroxy-7-methyl-4-(4H-[1,2,4]triazol-3-yl)-octyl]-amide

To a solution of acetic acid6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-3-(4H-[1,2,4]triazol-3-yl)-heptylester (575 mg, 1.08 mmol) in methanol (10 mL) was added potassiumcarbonate (276 mg, 2.00 mmol), stirred for 5 hours, and concentrated.The crude product was dissolved in ethyl acetate and water. The organiclayer was then washed with saturated aqueous sodium chloride, dried oversodium sulfate, filtered and concentrated. Chromatography on silica gelgave the title compound (459 mg, 87%).

The title compounds for examples 17-18 were prepared by a methodanalogous to that described in Example 16.

EXAMPLE R¹ R² R³ R⁴ 17

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EXAMPLE 19

Quinoxaline-2-carboxylic acid[1-benzyl-4-(4,5-dihydro-1H-imidazol-2-yl)-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

Quinoxaline-2-carboxylic acid[1-benzyl-4-(4,5-dihydro-1H-imidazol-2-yl)-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

To a solution of ethylenediamine (0.040 mL, 0.598 mmol) in toluene (2mL) at −10° C. was added trimethylaluminum (2.0 M in hexanes, 0.300 mL,0.600 mmol) and stirred for 15 minutes. A solution ofquinoxaline-2-carboxylic acid{1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide(250 mg, 0.556 mmol) in toluene (3 mL) was then added and the reactionwarmed to ambient temperature, then heated to reflux for 3 hours. Thereaction was cooled to ambient temperature and quenched carefully withwater (1 mL). The solution was diluted with methylene chloride andmethanol and then filtered, washing the filtrate with methanol. Theorganics were concentrated and the crude product was purified bychromatography on silica gel to give the title compound (74 mg, 17%).

The title compounds for examples 20-21 were prepared by a methodanalogous to that described in Example 19.

EXAMPLE R¹ R² R³ R⁴ 20

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EXAMPLE 22

Quinoxaline-2-carboxylic acid [4-(5-amino-[1,3,4]oxadiazol-2-yl)-1-benzyl-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

Quinoxaline-2-carboxylic acid(1-benzyl-7-fluoro-4-hydrazinocarbonyl-2-hydroxy-7-methyl-octyl)-amide

To a solution of quinoxaline-2-carboxylic acid{1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide(220 mg, 0.489 mmol) in methanol (5 mL) was added excess hydrazine(0.500 mL) and stirred for 18 hours. The reaction was concentrated togive the title compound (222 mg, 94%).

Quinoxaline-2-carboxylic acid [4-(5-amino-[1,3,4]oxadiazol-2-yl)-1-benzyl-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

To a solution of quinoxaline-2-carboxylic acid(1-benzyl-7-fluoro-4-hydrazinocarbonyl-2-hydroxy-7-methyl-octyl)-amide(110 mg, 0.228 mmol) in dioxane (0.5 mL) and water (0.5 mL) was addedcyanogen bromide (31 mg, 0.296 mmol) and potassium hydrogencarbonate (31mg, 0.310 mmol). The reaction was heated to reflux for 1 hour thencooled to ambient temperature. The dioxane/water was removed by addingbenzene (5 mL) and concentrating (2×). The remaining solid was dissolvedin ethyl acetate and water. The layers were separated and the aqueouslayer extracted with ethyl acetate. The combined organics were driedover sodium sulfate and concentrated. Recrystallization of the crudeproduct using a mixture of ethyl acetate, hexanes and methanol gave thetitle compound (64 mg, 55%).

The title compounds for examples 23-33 were prepared by a methodanalogous to that described in Example 22.

EXAMPLE R¹ R² R³ R⁴ 23

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EXAMPLE 34

Quinoxaline-2-carboxylic acid[1-benzyl-7-fluoro-2-hydroxy-7-methyl-4-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-octyl]-amide

Quinoxaline-2-carboxylic acid[1-benzyl-7-fluoro-2-hydroxy-7-methyl-4-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-octyl]-amide

To a solution of quinoxaline-2-carboxylic acid(1-benzyl-7-fluoro-4-hydrazinocarbonyl-2-hydroxy-7-methyl-octyl)-amide(62 mg, 0.129 mmol) in tetrahydrofuran (2 mL) was added triethylamine(0.018, 0.129 mmol) at 0° C. was added carbonyldiimidazole (23 mg, 0.142mmol). The reaction was allowed to warm to ambient temperature andstirred a total of 20 hours before diluting with ethyl acetate (10 mL)and hexane (2 mL). The mixture was washed with saturated aqueousammonium chloride, saturated aqueous sodium bicarbonate, and saturatedaqueous sodium chloride. The organic layer was dried over magnesiumsulfate, filtered and concentrated. Chromatography on silica gel gavethe title compound (54 mg, 82%).

The title compounds for examples 35-36 were prepared by a methodanalogous to that described in Example 34.

EXAMPLE R¹ R² R³ R⁴ 35

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EXAMPLE 37

Quinoxaline-2-carboxylic acid[1-benzyl-4-(4,5-dihydro-oxazol-2-yl)-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

2-(3-Fluoro-3-methy-butyl)-4-hydroxy-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoicacid

To a solution of quinoxaline-2-carboxylic acid{1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide(4 g, 8.90 mmol) in tetrahydrofuran was added lithium hydroxide (1 M inwater, 28 mL) and stirred for 2 hours. The reaction was thenconcentrated, and concentrated from benzene (2×) to give the titlecompound (4.2 g, 100%).

4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-3-methyl-butyl)-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoicacid

To a solution of2-(3-fluoro-3-methyl-butyl)-4-hydroxy-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoicacid (1.63 g, 3.49 mmol) in dimethylformamide (10 mL) was addedt-butyldimethylsilyl choride (3.2 g, 20.9 mmol) and imidazole (2.9 g,41.9 mmol). The reaction was stirred for 4 days then quenched withmethanol and stirred another 0.5 hours. The solution was diluted withether and water. The organic layer was washed with saturated aqueoussodium chloride, dried over magnesium sulfate, filtered andconcentrated. Chromatography on silica gel gave the title compound (784mg, 39%).

Quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-4-(2-hydroxy-ethylcarbamoyl)-7-methyl-octyl]-amide

To a solution of4-(tert-butyl-dimethyl-silanyloxy)-2-(3-fluoro-3-methyl-butyl)-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoicacid (515 mg, 0.885 mmol) in methylene chloride (9 mL) was addedethanolamine (0.080 mL, 1.33 mmol), 1-hydroxybenzotriazole (215 mg, 1.59mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288mg, 1.50 mmol) and triethylamine (0.247 mL, 1.77 mmol). The resultingsolution was stirred for 17 hours then diluted with ethyl acetate andwashed with water then saturated aqueous sodium chloride. The organiclayer was then dried over sodium sulfate, filtered, and concentrated.Chromatography on silica gel gave the title compound (343 mg, 62%).

Quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-4-(45-dihydro-oxazol-2-yl)-7-fluoro-7-methyl-octyl]-amide

To a solution of quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanytoxy)-7-fluoro-4-(2-hydroxy-ethylcarbamoyl)-7-methyl-octyl]-amide(100 mg, 0.160 mmol) in methylene chloride (1.5 mL) was addedtriphenylphosphine (63 mg, 0.240 mmol), hexachloroethane (57 mg, 0.240mmol), and triethylamine (0.045 mL, 0.320 mmol). The on was stirred for2 hours than chromatographed directly on silica gel to give the titlecompound (72.5 mg, 75%).

Quinoxaline-2-carboxylic acid [1-benzyl-4-(4,5-dihydro-oxazol-2-yl)-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

To a solution of quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-4-(4,5-dihydro-oxazol-2-yl)-7-fluoro-7-methyl-octyl]-amide(41 mg, 0.068 mmol) in tetrahydrofuran (0.70 mL) was addedtris(dimethylamino)sulfur (trimethylsilyl)difluoride (56 mg, 0.203mmol). The reaction was stirred for 1 hour then quenched with methanoland concentrated. Chromatography on silica gel gave the title compound(27.8 mg, 84%).

The title compounds for examples 38-49 were prepared by a methodanalogous to described in Example 37.

EXAMPLE R¹ R² R³ R⁴ 38

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EXAMPLE 50

Quinoxaline-2-carboxylic acid(1-benzyl-7-fluoro-2-hydroxy-7-methyl-4-oxazol-2-yl-octyl)-amide

Quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-7-methyl-4-(2-oxo-ethylcarbamoyl)-octyl]-amide

To a solution of quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-4-(2-hydroxy-ethylcarbamoyl)-7-methyl-octyl]-amide(250 mg, 0.400 mmol) in methylene chloride was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one [Dess-Martinperiodinane] (340 mg, 0.800 mmol). The reaction was stirred for 2 hoursand then diluted with ether and quenched with a 1:1 mixture of saturatedaqueous sodium thiosulfate:sodium bicarbonate. The layers were separatedand the aqueous layer extracted with ethyl acetate. The combinedorganics were washed with a 1:1 mixture of saturated aqueous sodiumthiosulfate:sodium bicarbonate, water, and saturated sodium chloride.The organic layer was then dried over sodium sulfate, filtered, andconcentrated. Chromatography on silica gel gave the title compound (233mg, 94%).

Quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-7-methyl-4-oxazol-2-yl-octyl]-amide

To a solution of quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-7-methyl-4-(2-oxo-ethylcarbamoyl)-octyl]-amide(230 mg, 0.369 mmol) in methylene chloride (3.5 mL) was addedtriphenylphosphine (145 mg, 0.554 mmol), hexachloroethane (131 mg, 0.554mmol) and triethylamine (0.103 mL, 0.739 mmol). The reaction was stirredfor 16 hours than concentrated. Chromatography on silica gel gave thetitle compound (137 mg, 62%).

Quinoxaline-2-carboxylic acid(1-benzyl-7-fluoro-2-hydroxy-7-methyl-4-oxazol-2-yl-octyl)-amide

To a solution of quinoxaline-2-carboxylic acid[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-7-methyl-4-oxazol-2-yl-octyl]-amide(133 mg, 0.220 mmol) in tetrahydrofuran (2 mL) was addedtris(dimethylamino)sulfur (trimethylsilyl)difluoride (180 mg, 0.660mmol). The reaction was stirred for 1 hour then quenched with methanoland concentrated. Chromatography on silica gel gave the title compound(73 mg, 68%).

The title compounds for examples 51-61 were prepared by a methodanalogous to that described in Example 50.

EXAMPLE R¹ R² R³ R⁴ 51

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EXAMPLE 62

Quinoxaline-2-carboxylic acid(4-benzenesulfonyl-1-benzyl-2-hydroxy-7-methyl-octyl)-amide

(4-Benzenesulfonyl-1-benzyl-2-hydroxy-7-methyl-octvl)-carbamic acidbenzyl ester

To a solution of 3.0 equivalents of(4-methyl-pentane-1-sulfonyl)-benzene (previously prepared by Gaoni, J.Org. Chem. 1982, 47, 2564) in tetrahydrofuran cooled to −78° C. is added3.0 equivalents of n-butyl lithium and stirred for 30 min. Oneequivalent of (1-oxiranyl-2-phenyl-ethyl)-carbamic acid benzyl ester(previously prepared by Kaldor, et al. J. Med. Chem., 1997, p. 3979) inTHF is then added dropwise and the reaction stirred for 1.5 h. Thereaction is then quenched with saturated aqueous sodium bicarbonate andwarmed to ambient temperature. After standard aqueous work-up andextraction, followed by concentration and silica gel chromatography thetitle compound is obtained.

2-Amino-5-benzenesulfonyl-8-methyl-1-phenyl-nonan-3-ol

To a solution of(4-benzenesulfonyl-1-benzyl-2-hydroxy-7-methyl-octyl)-carbamic acidbenzyl ester in ethanol is added 10 mole % palladium hydroxide oncarbon. The mixture is then shaken on a Parr shaker under 50 psi ofhydrogen for approximately 18 h. The catalyst is filtered off and thesolution concentrated to give the title compound.

Quinoxaline-2-carboxylic acid(4-benzenesulfonyl-1-benzyl-2-hydroxy-7-methyl-octyl)-amide

To a solution of one equivalent of2-amino-5-benzenesulfonyl-8-methyl-1-phenyl-nonan-3-ol in methylenechloride is added 1.05 equivalents each of 2-quinoxalinecarboxylic acid,N-methyl morpholine, andO-benzotriazol-1-yl-N,N,N′,N′-teteramethyluronium hexafluorophosphate.The reaction mixture is stirred at ambient temperature for 18 h. Afterstandard aqueous work-up and extraction, followed by concentration andsilica gel chromatography the title compound is obtained.

The title compounds for examples 63-72 are prepared by a methodanalogous to that described in Example 62.

EXAMPLE R¹ R² R³ R⁴ 63

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EXAMPLE 73

Quinoxaline-2-carboxylic acid(1-benzyl-7-fluoro-2-hydroxy-7-methyl-4-thiocarbamoyl-octyl)-amide

Acetic acid6-fluoro-6-methyl-1-2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl-3-thiocarbamoyl-heptylester

To a solution of 1.0 equivalent of acetic acid3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptylester in tetrahydrofuran cooled to 0° C. is added 0.5 equivalents ofLawesson's reagent dropwise. The yellow suspension is allowed to warm toroom temperature and stirred for about 5 h. The reaction mixture isconcentrated to dryness, then purified by silica gel chromatography togive the title compound.

Quinoxaline-2-carboxylic acid(1-benzyl-7-fluoro-2-hvdroxy-7-methyl-4-thiocarbamoyl-octyl)-amide

To a solution of 1.0 equivalents of acetic acid6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-3-thiocarbamoyl-heptylester in methanol is added 2.0 equivalents of potassium carbonate,stirred for approximately 5 hours, and concentrated. The crude productis dissolved in ethyl acetate and water. The organic layer is thenwashed with saturated aqueous sodium chloride, dried over sodiumsulfate, filtered and concentrated. Chromatography on silica gel givesthe title compound.

The title compounds for examples 74-76 are prepared by a methodanalogous to that described in Example 73.

EXAMPLE R¹ R² R³ R⁴ 74

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EXAMPLE 77

Quinoxaline-2-carboxylic acid(1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide

Acetic acid3-carbamimidoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptylester

To a solution of acetic acid6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-3-thiocarbamoyl-heptylester in acetone is added excess methyl iodide. The reaction is thenrefluxed for approximately 2 h, then cooled and concentrated. The crudeproduct is taken up in saturated solution of ammonia in methanol andstirred for approximately 15 hrs. The reaction mixture is concentratedto dryness, then purified by silica gel chromatography to give the titlecompound.

Quinoxaline-2-carboxylic acid(1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide

To a solution of 1.0 equivalents of acetic acid3-carbamimidoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptylester in methanol is added 2.0 equivalents of potassium carbonate,stirred for approximately 5 hours, and concentrated. The crude productis dissolved in ethyl acetate and water. The organic layer is thenwashed with saturated aqueous sodium chloride, dried over sodiumsulfate, filtered and concentrated. Chromatography on silica gel givesthe title compound.

The title compounds for examples 78-80 are prepared by a methodanalogous to that described in Example 77.

EXAMPLE R¹ R² R³ R⁴ 78

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EXAMPLE 81

Quinoxaline-2-carboxylic acid[4-(acetylimino-amino-methyl)-1-benzyl-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

Quinoxaline-2-carboxylic acid[4-(acetylimino-amino-methyl)-1-benzyl-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid(1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide inmethylene chloride is added 1.0 equivalents of triethylamine followed by1.0 equivalents of acetyl chloride. The reaction is stirred at ambienttemperature for approximately 5 hours. After standard aqueous work-upand extraction, followed by concentration and silica gel chromatographythe title compound is obtained.

The title compounds for examples 82-86 are prepared by a methodanalogous to that described in Example 81.

EXAMPLE R¹ R² R³ R⁴ 82

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EXAMPLE 87

Quinoxaline-2-carboxylic acid[4-(amino-methanesulfonylimino-methyl)-1-benzyl-1-fluoro-2-hydroxy-7-methyl-octyl]-amide

Quinoxaline-2-carboxylic acid[4-(amino-methanesulfonylimino-methyl)-1-benzyl-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid(1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide inmethylene chloride is added 1.0 equivalents of triethylamine followed by1.0 equivalents of methanesulfonyl chloride. The reaction is stirred atambient temperature for approximately 5 hours. After standard aqueouswork-up and extraction, followed by concentration and silica gelchromatography the title compound is obtained.

The title compounds for examples 88-94 are prepared by a methodanalogous to that described in Example 87.

EXAMPLE R¹ R² R³ R⁴ 88

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EXAMPLE 95

Quinoxaline-2-carboxylic acid[4-(cyanoimino-amino-methyl)-1-benzyl-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

Quinoxaline-2-carboxylic acid[4-(cyanoimino-amino-methyl)-1-benzyl-7-fluoro-2-hydroxy-7-methyl-octyl]-amide

To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid(1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide inmethylene chloride is added 1.0 equivalents of cyanogen bromide. Thereaction is stirred at ambient temperature for approximately 15 hours.After standard aqueous work-up and extraction, followed by concentrationand silica gel chromatography the title compound is obtained.

The title compounds for examples 96-98 are prepared by a methodanalogous to that described in Example 95.

EXAMPLE R¹ R² R³ R⁴ 96

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What is claimed is:
 1. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R¹ isquinoxalinyl optionally substituted with one or more substituentsindependently selected from the group consisting of hydrogen, deuterium,halo, CN, (C₁-C₆)alkyl optionally substituted with one or more fluorineatoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionallysubstituted with one or more fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl, (C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl],(C₁-C₆)alkyl, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—, H₂N—SO₂—(C₁-C₆)alkyl,(C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl,CF₃SO₃—, (C₁-C₆)alkyl-SO₃—,phenyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; R² is phenyl-(CH₂)_(m)—,naphthyl-(CH₂)_(m)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(m)—, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl-(CH₂)_(m)—, wherein m is an interger from zero tofour; wherein each of said phenyl, naphthyl, (C₃-C₁₀)cycloalkyl or(C₂-C₉)heteroaryl moieties of said phenyl-(CH₂)_(m)—,naphthyl-(CH₂)_(m)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(m)— or(C₂-C₉)heteroaryl-(CH₂)_(m)—groups may optionally be substituted withone or more substituents independently selected from hydrogen,deuterium, halo, CN, (C₁-C₆)alkyl optionally substituted with one ormore fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆) alkyl-HN(C═O )—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═C)—NH,(C₁-C₆)alkyl(C═C)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—,H₂N—SO_(2—, H) ₂N—SO₂(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C_(6)alkyl-SO) ₃—,phenyl, phenoxy, benzyloxy, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,and (C₂-C₉)heteroaryl; R³ is hydrogen, deuterium, (C₁-C₁₀)alkyl,(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—, (C₂-C₉)heterocycloalkyl-(CH₂)_(n)—,(C₂-C₉)heteroayl-(CH₂)_(n)— or aryl-(CH₂)_(n)—; wherin n is an intergerfrom zero to six; wherein said R³ (C₁-C₁₀)alkyl group may optionally besubstituted with one or more substituents, independently selected fromhydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionally substituted withone or more fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO_(2—(C) ₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—,phenyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and(C₂-C₉)heteroaryl; and wherein any of the carbon—carbon single bonds ofsaid (C₁-C₁₀)alkyl may optionally be replaced by a carbon—carbon doublebond; wherein the (C₃-C₁₀)cycloalkyl moiety of said R³(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—group may optionally be substituted by oneto three substitutents independently selected from the group consistingof hydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionally substitutedwith one or more fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy optionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-c₆)alkyl,H(O═C)—H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—,(C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino (C₁-C₆)alkylamino[(C₁-C₆)alkyl]₂amino, amino (C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂N—(C═O), H₂N(C═O)—(C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl(S═O)—, (S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—,H₂N—SO₂—, H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,and (C₂-C₉)heteroaryl;wherein the (C₂-C₉)heterocycloalkyl moiety of said R³(C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group has from one to threeheteroatoms independently selected from nitrogen, sulfur,oxygen, >S(═O), >SO₂ or >NR⁶, wherein said (C₂-C₉)heterocycloalkylmoiety of said (C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may optionallybe substituted on any of the ring carbon atoms capable of forming anadditional bond with a substituent independently selected from the groupconsisting of hydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionallysubstituted with one or more fluorine atoms, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one ormore fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkylHN—SO₂—, (C₁-C₆)alkyl-SO₂—NH—,H₂N—SO₂—, H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;wherein the (C₂-C₉)heteroaryl moiety of said R³(C₂-C₉)heteroaryl-(CH₂)_(n)— group has from one to three heteroatomsindependently selected from nitrogen, sulfur or oxygen wherein said(C₂-C₉)heteroaryl moiety of said (C₂-C₉)heteroaryl-(CH₂)_(n)— group mayoptionally be substituted on any of the ring carbon atoms capable offorming an additional bond with a substituent selected from the groupconsisting of hydrogen, deuterium, halo, CN, (C₁-C₆)alkyl optionallysubstituted with one or more fluorine atoms, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one ormore fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; andwherein said aryl moiety of said R³ aryl-(CH₂)_(n)— group is optionallysubstituted phenyl or naphthyl, wherein said phenyl and naphthyl mayoptionally be substituted with from one to three substituentsindependently selected from the group consisting of hydrogen, deuterium,halo, CN, (C₁-C₆)alkyl optionally substituted with one or more fluorineatoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionallysubstituted with one or more fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl-S—, (C₁-C₆)alkyl,(C₁-C₆)alkyl-S—, (C₁-C₆) alkyl-(S═O)—(C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—, H₂N—SO₂—(C₁-C₆)alkyl,(C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl,CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; and R⁴ is(C₂-C₉)heteroaryl , (C₂-C₉)heterocycloalkyl, R⁵R⁶N-sulfonyl or a groupof the formula

wherein R⁵ is hydrogen, deuterium, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C═O)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(p)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(p)—, (C₂-C₉)heteroaryl-(CH₂)_(p)—,phenyl-(CH₂)_(p)—, or naphthyl-(CH₂)_(p)—, wherein p is an integer fromzero to four; wherein said (C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl,phenyl and naphthyl groups of said (C₂-C₉)heterocycloalkyl-(CH₂)_(p)—,(C₂-C₉)heteroaryl-(CH₂)_(p)—, phenyl-(CH₂)_(p)—, or naphthyl-(CH₂)_(p)—may be optionally substituted on any of the ring atoms capable ofsupporting an additional bond with a substituent selected from the groupconsisting of hydrogen, halo, CN, (C₁-C₆)alkyl optionally substitutedwith one or more fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, optionally substituted with one or more fluorine atoms,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆) alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—, (C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH, (C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; orR⁵ and R⁶ together with the nitrogen atom to which they are attachedform a (C₂-C₉)heterocycloalkyl group wherein any of the ring atoms ofsaid (C₂-C₉)heterocycloalkyl group may optionally be substituted with asubstituent selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl optionally substituted with one or more fluorine atoms,hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted withone or more fluorine atoms, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino (C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; R⁶is hydrogen, deuterium, (C₁-C₆)alkyl or amino; X is NR⁷ or S wherein R⁷is defined as R⁴ above; and with the proviso that when R⁴ is afive-membered heterocyclic group, either R² or R³ must be substituted bya functional group other than (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═0)—O—, (C₁-C₆)alkyl-(C═0)—O—(C₁-C₆)alkyl,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,benzofuryl, indolyl, azacycloalkyl, azabicycloalkyl or benzopiperidinyl.2. A compound according to claim 1, wherein said compound of formula Ihas the exact stereochemistry depicted in formula

wherein R¹, R², R³, R⁴ and R⁵ are as described in claim
 1. 3. A compoundaccording to claim 1, wherein R¹ is optionally substitutedquinoxalin-2-yl or quinoxalin-6-yl.
 4. A compound according to claim 2,wherein R¹ is optionally substituted quinoxalin-2-yl or quinoxalin-6-yl.5. A compound according to claim 1, wherein R² is optionally substitutedbenzyl.
 6. A compound according to claim 2, wherein R² is optionallysubstituted benzyl.
 7. A compound according to claim 3, wherein R² isoptionally substituted benzyl.
 8. A compound according to claim 4,wherein R² is optionally substituted benzyl.
 9. A compound according toclaim 1, wherein R³ is optionally substituted (C₁-C₁₀)alkyl or(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—.
 10. A compound according to claim 2,wherein R³ is optionally substituted (C₁-C₁₀)alkyl or(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—.
 11. A compound according to claim 4,wherein R³ is optionally substituted (C₁-C₁₀)alkyl or (C₃-C₁₀)cycloalkyl-(CH₂)_(n)—.
 12. A compound according to claim 3, wherein R³is optionally substituted (C₁-C₁₀)alkyl or(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—.
 13. A compound according to claim 1,wherein R³ is optionally substituted n-butyl, t-butyl, isobutyl,n-pentyl, 2methyl-pentyl, cyclopentyl, or cyclohexl.
 14. A compoundaccording to claim 2, wherein R³ is optionally substituted n-butyl,t-butyl, isobutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, orcyclohexyl.
 15. A compound according to claim 6, wherein R³ isoptionally substituted n-butyl, t-butyl, isobutyl, n-pentyl,2methyl-pentyl, cyclopentyl, or cyclohexyl.
 16. A compound according toclaim 3 wherein R³ is optionally substituted n-butyl, t-butyl, isobutyl,n-pentyl, 2-methyl-pentyl, cyclopentyl, or cyclohexyl.
 17. A compoundaccording to claim 1, wherein R³ is substituted by fluoro or hydroxy.18. A compound according to claim 2, wherein R³ is substituted by fluoroor hydroxy.
 19. A compound according to claim 1, wherein R³ is4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or1-hydroxy-cyclohexyl.
 20. A compound according to claim 2, wherein R³ is4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or1-hydroxy-cyclohexyl.
 21. A compound according to claim 6, wherein R³ is4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or1-hydroxy-cyclohexyl.
 22. A compound according to claim 3 wherein R³ is4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or1-hydroxy-cyclohexyl.
 23. A compound according to claim 8 wherein R³ is4,4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl, or1-hydroxy-cyclohexyl.
 24. A compound according to claim 1, wherein saidcompound is: Quinoxaline-2-carboxylic acid[1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[1(S)-benzyl-2(S),7-dihydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-4(R)-sulfamoyl-octyl]-amide;Quinoxaline-2-carboxylic acid(1(S)-benzyl-2(S),7-dihydroxy-7-methyl-4(R)-sulfamoyl-octyl)-amide;Quinoxaline-2-carboxylic acid[7-fluoro-1(S)-(3-fluoro-benzyl)-2(S),-hydroxy-7-methyl-4(R)-sulfamoyl-octyl]-amide;Quinoxaline-2-carboxylic acid(1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-sulfamoyl-octyl)-amide;Quinoxaline-2-carboxylic acid [1(S)-(3-fluoro-benzyl)-(2(S),7-dihydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;Quinoxaline-2-carboxylic acid(1(S)-benzyl-2(S)-7-dihydroxy-7-methyl-4(R)-methylsulfamoyl-octyl)-amide;Quinoxaline-2-carboxylic acid[(S)-(3-fluoro-benzyl)-2(S),7-hydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;Quinoxaline-2-carboxylic acid[I(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-methylsulfamoyl-octyl)-amide;Quinoxaline-2-carboxylic acid [4(R)-(4-chloro-1H-imidazol-2-yl)-1(S)-(3-fluoro-benzyl)-2(S),-7-fluoro-benzyl)-2(S)-hydroxy-dihydroxy-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[1(S)-benzyl-4(R)(4-chloro-1H-imidazol-2-yl)-2(S),-7-hydroxy-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[4(R)-(4-chloro-1H-imidazol-2-yl)-7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[1(S)-benzyl-4(R)(4-chloro-1H-imidazol-2-yl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[1(S)-(3-fluoro-benzyl)-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;Quinoxaline-2-carboxylic acid[1(S)-benzyl-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-7-dihydroxy-7-methyl-octyl]amide;Quinoxaline-2-carboxylic acid[7-fluoro-1(S)-(3-fluoro-benzyl)-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-hydroxy-7-methyl-octyl]-amide;and Quinoxaline-2-carboxylic acid[1(S)-benzyl-7-fluoro-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-hydroxy-7-methyl-octyl]amide.